Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study.

Importance The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Objective To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). Design, Setting, and Participants A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. Main Outcomes and Measures A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. Results The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. Conclusions and Relevance These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

[1]  Publisher Excellent Publishers.  International Journal of Current Microbiology and Applied Sciences , 2020 .

[2]  Xiao-wen Li,et al.  erbb4 Deficits in Chandelier Cells of the Medial Prefrontal Cortex Confer Cognitive Dysfunctions: Implications for Schizophrenia. , 2019, Cerebral cortex.

[3]  N. Swerdlow,et al.  Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care , 2018, Schizophrenia Research.

[4]  K. Hamacher,et al.  HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond , 2018, Brain : a journal of neurology.

[5]  G. Washko,et al.  Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease , 2018, Human Genomics.

[6]  I. Deary,et al.  Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia , 2016, Molecular Psychiatry.

[7]  N. Swerdlow,et al.  Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next , 2016, Journal of psychopharmacology.

[8]  N. Popov,et al.  Characterization of Micro RNA Signature in Peripheral Blood of Schizophrenia Patients using µParafloTM miRNA Microarray Assay , 2016 .

[9]  C. Obie,et al.  Neuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders , 2016, Molecular Neuropsychiatry.

[10]  Thomas C. Südhof,et al.  Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons , 2016, Science.

[11]  Jonathan P. Beauchamp,et al.  Genome-wide association study identifies 74 loci associated with educational attainment , 2016, Nature.

[12]  Robert W. Mills,et al.  Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures , 2016, eLife.

[13]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.

[14]  Michael F. Green,et al.  Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study , 2016, Schizophrenia Research.

[15]  Ilana Belitskaya-Lévy,et al.  Solutions for quantifying P-value uncertainty and replication power , 2016, Nature Methods.

[16]  Giulio Genovese,et al.  Schizophrenia risk from complex variation of complement component 4 , 2016, Nature.

[17]  Qing Jun Wang,et al.  Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease) , 2016, Annals of the New York Academy of Sciences.

[18]  E. Chang,et al.  Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse , 2016, Neuron.

[19]  Kosha Ruparel,et al.  The Philadelphia Neurodevelopmental Cohort: constructing a deep phenotyping collaborative. , 2015, Journal of child psychology and psychiatry, and allied disciplines.

[20]  L. Sun,et al.  Gene expression profiling in peripheral blood mononuclear cells of early-onset schizophrenia , 2015, Genomics data.

[21]  Michael F. Green,et al.  Neurocognitive performance in family-based and case-control studies of schizophrenia , 2015, Schizophrenia Research.

[22]  D. Braff.  The importance of endophenotypes in schizophrenia research , 2015, Schizophrenia Research.

[23]  Michael F. Green,et al.  Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies , 2015, Schizophrenia Research.

[24]  Michael F. Green,et al.  California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: Comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS) , 2015, Schizophrenia Research.

[25]  Michael F. Green,et al.  Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) Study: The moderating role of smoking status and antipsychotic medications , 2015, Schizophrenia Research.

[26]  Michael F. Green,et al.  Attention/vigilance in schizophrenia: Performance results from a large multi-site study of the Consortium on the Genetics of Schizophrenia (COGS) , 2015, Schizophrenia Research.

[27]  Qing Lu,et al.  Imbalance of HCN1 and HCN2 expression in hippocampal CA1 area impairs spatial learning and memory in rats with chronic morphine exposure , 2015, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[28]  A. Law,et al.  Transient Overexposure of Neuregulin 3 during Early Postnatal Development Impacts Selective Behaviors in Adulthood , 2014, PloS one.

[29]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[30]  Oriane Trouillard,et al.  De novo mutations in HCN1 cause early infantile epileptic encephalopathy , 2014, Nature Genetics.

[31]  Raphael T. Gerraty,et al.  Neuroimaging predictors of cognitive performance across a standardized neurocognitive battery. , 2014, Neuropsychology.

[32]  J. Callicott,et al.  Effects of Neuregulin 3 Genotype on Human Prefrontal Cortex Physiology , 2014, The Journal of Neuroscience.

[33]  L. Lazzeroni,et al.  P-values in genomics: Apparent precision masks high uncertainty , 2014, Molecular Psychiatry.

[34]  I. Deary,et al.  Molecular Genetic Evidence for Genetic Overlap between General Cognitive Ability and Risk for Schizophrenia: A Report from the Cognitive Genomics Consortium (COGENT) , 2013, Molecular Psychiatry.

[35]  G. Pearlson,et al.  Clinical phenotypes of psychosis in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). , 2013, The American journal of psychiatry.

[36]  N. Wray,et al.  Correction: Novel Genetic Analysis for Case-Control Genome-Wide Association Studies: Quantification of Power and Genomic Prediction Accuracy , 2013, PLoS ONE.

[37]  Christine M Constantinople,et al.  Prefrontal Cortex HCN1 Channels Enable Intrinsic Persistent Neural Firing and Executive Memory Function , 2013, The Journal of Neuroscience.

[38]  L. Siever,et al.  Spatial and Temporal Mapping of De Novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network , 2013, Cell.

[39]  F. Alkuraya,et al.  Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. , 2013, Human molecular genetics.

[40]  Michael F. Green,et al.  Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. , 2013, The American journal of psychiatry.

[41]  P. Wong,et al.  Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients , 2013, Translational Psychiatry.

[42]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[43]  S Cichon,et al.  Genome-wide association of mood-incongruent psychotic bipolar disorder , 2012, Translational Psychiatry.

[44]  D. Johnston,et al.  Enhancement of Dorsal Hippocampal Activity by Knockdown of HCN1 Channels Leads to Anxiolytic- and Antidepressant-like Behaviors , 2012, Neuron.

[45]  S Purcell,et al.  De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia , 2011, Molecular Psychiatry.

[46]  Michael F. Green,et al.  Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. , 2011, The American journal of psychiatry.

[47]  A. Jablensky,et al.  Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition , 2011, Molecular Psychiatry.

[48]  D. Johnston,et al.  Deletion of the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Auxiliary Subunit TRIP8b Impairs Hippocampal Ih Localization and Function and Promotes Antidepressant Behavior in Mice , 2011, The Journal of Neuroscience.

[49]  Daniel R Weinberger,et al.  Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain , 2010, Proceedings of the National Academy of Sciences.

[50]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[51]  Karin E. Borgmann-Winter,et al.  Scents and nonsense: olfactory dysfunction in schizophrenia. , 2009, Schizophrenia bulletin.

[52]  J. McGrath,et al.  Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. , 2009, American journal of human genetics.

[53]  P. Szeszko,et al.  Gray matter structural alterations in psychotropic drug-naive pediatric obsessive-compulsive disorder: an optimized voxel-based morphometry study. , 2008, The American journal of psychiatry.

[54]  A. Singleton,et al.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2008, Science.

[55]  Zachary A. Szpiech,et al.  Genotype, haplotype and copy-number variation in worldwide human populations , 2008, Nature.

[56]  Michael F. Green,et al.  The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. , 2008, The American journal of psychiatry.

[57]  C. Tamminga,et al.  Comparing genes and phenomenology in the major psychoses: schizophrenia and bipolar 1 disorder. , 2007, Schizophrenia bulletin.

[58]  Michael F. Green,et al.  Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. , 2007, Archives of general psychiatry.

[59]  C. DeCarli,et al.  Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study , 2007, BMC Medical Genetics.

[60]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[61]  R. McGinnis,et al.  Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia , 2007 .

[62]  Daniel R Weinberger,et al.  expression in the brain , 2006 .

[63]  B. Turetsky,et al.  Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. , 2006, Schizophrenia bulletin.

[64]  Raquel E Gur,et al.  The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. , 2006, Schizophrenia bulletin.

[65]  Michael F. Green,et al.  The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration. , 2006, Schizophrenia bulletin.

[66]  Manzar Ashtari,et al.  White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study. , 2005, Journal of the American Academy of Child and Adolescent Psychiatry.

[67]  P. Sullivan,et al.  The Genetics of Schizophrenia , 2005, PLoS medicine.

[68]  N. Craddock,et al.  The beginning of the end for the Kraepelinian dichotomy , 2005, British Journal of Psychiatry.

[69]  T. Gilliam,et al.  Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia , 2004, Molecular Psychiatry.

[70]  Matthew F. Nolan,et al.  A Behavioral Role for Dendritic Integration HCN1 Channels Constrain Spatial Memory and Plasticity at Inputs to Distal Dendrites of CA1 Pyramidal Neurons , 2004, Cell.

[71]  L. Almasy,et al.  Novel family‐based approaches to genetic risk in thrombosis , 2003, Journal of thrombosis and haemostasis : JTH.

[72]  H. Stefánsson,et al.  Neuregulin 1 and susceptibility to schizophrenia. , 2002, American journal of human genetics.

[73]  D. Attwell,et al.  The Amino Terminus of the Glial Glutamate Transporter GLT-1 Interacts with the LIM Protein Ajuba , 2002, Molecular and Cellular Neuroscience.

[74]  H. Yoneda,et al.  Paracentric inversion of chromosome 9 with schizoaffective disorder , 1997, Clinical genetics.

[75]  A. Hille-Rehfeld.  Mannose 6-phosphate receptors in sorting and transport of lysosomal enzymes. , 1995, Biochimica et biophysica acta.

[76]  J. Moeschler,et al.  Schizophrenia and mental retardation in an adult male with a de novo interstitial deletion 9(q32q34.1). , 1991, Journal of medical genetics.